Full Genome Viral Sequences Inform Patterns of SARS-Cov-2 Spread Into and Within Israel

Home , Barzilai Medical Center, Holon

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Full genome viral sequences inform patterns of SARS-CoV-2 spread into and within Israel

Danielle Miller1*, Michael A. Martin2,3*, Noam Harel1*, Talia Kustin1*, Omer Tirosh1*, Moran Meir1, Nadav Sorek4, Shiraz Gefen-Halevi5, Sharon Amit5, Olesya Vorontsov6, Dana Wolf6, Avi Peretz7,8, Yonat Shemer-Avni9, Diana Roif-Kaminsky10, Na’ama Kopelman11, Amit Huppert12,13, Katia Koelle2, Adi Stern1,14

1 School of Molecular Cell Biology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Israel 2 Department of Biology, Emory University, Atlanta, GA, USA 3 Population Biology, Ecology, and Evolution Graduate Program, Laney Graduate School, Emory University, Atlanta, GA, USA 4 Microbiology laboratory, Assuta Ashdod University-Affiliated Hospital. Ashdod, Israel 5 Clinical Microbiology Laboratory, Sheba Medical Center, Ramat-Gan, Israel 6 Clinical Virology Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel. 7 The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel 8 Clinical Microbiology Laboratory, The Baruch Padeh Medical Center, Poriya, Tiberias, Israel 9 Clinical Virology Laboratory, Soroka Medical Center and the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel 10 Microbiology Division, Barzilai University Medical Center, Ashkelon, Israel 11 Department of Computer Science, Holon Institute of Technology, Holon, Israel 12 Bio-statistical and Bio-mathematical Unit, The Gertner Institute for Epidemiology and, Health Policy Research, Chaim Sheba Medical Center, Tel Hashomer, 52621 Israel 13 School of Public Health, the Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, 69978 Israel 14 Edmond J. Safra Center for Bioinformatics at Tel Aviv University * Co-equal authorship

ABSTRACT Full genome sequences are increasingly used to track the geographic spread and transmission dynamics of viral pathogens. Here, with a focus on Israel, we sequenced 212 SARS-CoV-2 sequences and use them to perform a comprehensive analysis to trace the origins and spread of the virus. A phylogenetic analysis including thousands of globally sampled sequences allowed us to infer multiple independent introductions into Israel, followed by local transmission. Returning travelers from the U.S. contributed dramatically more to viral spread relative to their proportion in incoming infected travelers. Using phylodynamic analysis, we estimated that the basic reproduction number of the virus was initially around ~2.0-2.6, dropping by two-thirds following the implementation of social distancing measures. A comparison between reported and model-estimated case numbers indicated high levels of transmission heterogeneity in SARS-CoV-2 spread, with between 1-10% of infected individuals resulting in 80% of secondary infections. Overall, our findings underscore the ability of this virus to efficiently transmit between and within countries, as well as demonstrate the effectiveness of social distancing measures for reducing its spread.

NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

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INTRODUCTION

In December 2019 an outbreak of severe respiratory disease was identified in Wuhan, China (Huang, et al. 2020). Shortly later, the etiological agent of the disease was identified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Zhou, et al. 2020; Zhu, et al. 2020), and the disease caused by the virus was named coronavirus disease 19 (COVID-19). The virus has since spread rapidly across the globe, causing a WHO-declared pandemic with social and economic devastation in many regions of the world. The infectious disease research community has quickly stepped up to the task of characterizing the virus and its replication dynamics, describing its pathogenesis, and tracking its movement through the human population. Parameterized epidemiological models have been particularly informative of how this virus has spread with and without control measures in place (e.g., Tian, et al. 2020), and have been used to project viral spread both in the short-term (Flaxman, et al. 2020) and in the more distant future (Kissler, et al. 2020).

Along with epidemiological analysis based on case reports and COVID-19 death data, sequencing of viral genomes has become a powerful tool in understanding and tracking the dynamics of infections (Volz, et al. 2013; Gardy and Loman 2018). So-called “genomic epidemiology” allows for effective reconstruction of viral geographical spread as well as estimation of key epidemiological quantities such as the basic reproduction number of a virus, its growth rate and doubling time, and patterns of disease incidence and prevalence. Such insights have been used to inform policy makers during various pathogen outbreaks, as occurred for example in the 2014-2016 outbreak of Ebola virus in West Africa (Khoury, et al. 2018; Armstrong, et al. 2019), and during this current SARS-CoV-2 pandemic (Bedford, et al. 2020; Fauver, et al. 2020).

Here, we set out to sequence SARS-CoV-2 from samples across the state of Israel, with the aim of gaining a better understanding of introductions of the virus into Israel, spread of the virus inside the country, and the epidemiology of the disease, including (a) the basic reproduction number of the virus before and after social distancing measures were implemented, and (b) the extent of viral superspreading within Israel. We sought to gain this understanding within the context of existing epidemiological knowledge, including that the first confirmed cases of SARS-CoV-2 infection in Israel were reported in early-February, followed by many identified SARS-CoV-2 cases in travelers returning to Israel mainly from Europe and the United States. Growth in the number of verified cases rapidly ensued, which led to increased measures of social distancing, including the cessation of passenger flights to Israel, school closure, and eventually a near complete lockdown across the entire state of Israel. Quarantining of returning travelers from Europe was implemented between February 26 and March 4, 2020, and subsequently all incoming travel to Israel was arrested on March 9. In the meantime, the rate of testing was ramped up, eventually reaching a rate of more than 1,500 tests per million people per day. The reported daily incidence and reported numbers of daily severe cases peaked around mid-April and have dropped steadily since then. Despite this knowledge, many questions remain: Which of the multiple SARS-CoV-2 introductions resulted in sustained local transmission? How did the virus spread across the state? What was the magnitude of the virus’s reproduction potential within Israel, and to what extent did control measures mitigate its spread? Here, through a comprehensive set of phylogenetic and phylodynamic analyses, we quantitatively address these questions.

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RESULTS & DISCUSSION In order to gain a better understanding of the dynamics of SARS-CoV-2 spread into and within Israel, we sequenced the virus from a cohort of patients representing a random sample across Israel, resulting in 212 full-genome SARS-CoV-2 sequences (Methods). A total of 224 unique single nucleotide variants (SNVs) were identified between the Wuhan reference sequence and this set of sequences from Israel. Figure 1 shows the distribution of identified SNVs along the genome and their counts in the sequenced samples. Of these SNVs, 141 were non-synonymous, 72 were synonymous, and the remaining 11 were in non- coding regions. One of the most abundantly detected SNVs was a non-synonymous variant D614G found in the spike protein, which was present in 90% of the sequences. This variant has generated much interest as it has been reported to potentially increase the transmissibility of the virus (Korber, et al. 2020). Of note however, the alternative hypothesis that the observed increases in this variant’s frequency is due to demographic considerations and genetic drift has not been ruled out.

Figure 1. Variation found in sequenced samples from Israel. Counts of identified SNVs across the SARS-CoV-2 genome.

We also found five different high confidence genomic deletions, spanning between one and eighteen nucleotides (Fig. 2) (Methods), each of which was found in one to two samples. Three of these five deletions occurred in multiples of three and were in-frame deletions or affected non-coding regions. Of the remaining two deletions, deletion #3 spanned ten nucleotides, and likely prevents the translation of ORF7a. Deletion #4 occurred at the end of ORF8 and causes the replacement of the last amino acid with an additional five amino acids. Notably, an 81 nt in-frame deletion in ORF7a has been previously reported (Holland, et al. 2020), as has been a 382 nt deletion in ORF8 (Su, et al. 2020), suggesting that the virus is to some extent tolerant to deletions in these ORFs.

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(A)

(B) # Genome Length ORF/Genomic Suggested effect Number Sample IDs Number of coordinates location of reads samples supporting found in deletion 1 686-694 9nt ORF1ab Deletion of 3 amino acids 2 2086008, 3575, 1852 polyprotein 130710157 2 3882-3899 18nt ORF1ab Deletion of 6 amino acids 2 2089839, 427, 605 polyprotein and an additional single 2089852 amino acid mutation 3 27387- 10nt End of ORF6 Stop codon of ORF6 is 1 13077726 3801 27396 and start of recreated. Start codon of ORF7a ORF7a is deleted with no in-frame replacement 4 28254 1nt End of ORF8 Last amino acid is replaced 1 2086033 2849 by a 5 amino acid addition 5 29746- 3nt 3’ UTR Non-coding, unknown 2 51137844, 42,147 29748 51141225 Figure 2. Deletions found in Israeli samples. (A) Maximum-likelihood tree of Israeli sequences highlighting sequences found with deletions that are color-coded and described in (B). A clade with three independent deletions occurring in four samples is boxed. The phylogeny displayed was created with the ggtree package (Yu, et al. 2017).

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When focusing on deletions that occurred in two samples, we noted that the two samples bearing deletion #1 were located in very remote clades on the phylogeny, suggesting that the deletion occurred two independent times. Deletion #5 on the other hand was present in two related samples that were sampled five days apart from each other. Deletions #2, #3 and #4 revealed an intriguing pattern: three independent deletions (one of which was present in two samples) were all part of the same clade that included eighteen samples (Fig. 2). One non-synonymous SNV defined this clade: S2430R in ORF1b which affects the non- structural protein NSP16. This protein has been reported to be a 2ʹO-methyl-transferase that enhances evasion of the innate immune system (Menachery, et al. 2014).

While further in-depth investigation of SARS-CoV-2 indels is clearly needed, at this point we conjecture that the deletions we detected are neutral or to some extent deleterious, and that deletions in SARS-CoV-2 are likely to occur frequently given the number of deletions detected in our samples.

Origins and transmission patterns in Israel We next set out to explore patterns of SARS-CoV-2 introduction into Israel. Figure 3 shows the time-resolved phylogeny inferred using the 214 Israeli sequences (212 sequenced here and two additional ones sequenced previously) in addition to 4,693 representative sequences from across the world. This phylogeny allowed us to characterize the major viral clades circulating within Israel and to infer the geographic sources and timing of virus introductions into the state. We found multiple introductions into Israel from both the U.S and Europe, the latter including mainly the U.K., France and Belgium. Over 70% of the clade introductions into Israel (confidence intervals ranging from ~50% to ~80%, see Methods) were inferred to have occurred from the U.S., while the remaining were mainly from Europe. During the entire epidemic in Israel, very close monitoring of all incoming infected travelers was imposed, and reports show that only ~27% of infected returning travelers were from the U.S. The discrepancy between these estimated proportions suggests that the travelers returning from the U.S. contributed substantially more to the spread of the virus in Israel than would be proportionally expected. This may have occurred due to the gap in policy that allowed returning non-European travelers to avoid quarantine until March 9, or due to different contact patterns of those who returned from the U.S. Moreover, this suggests that had flights from the U.S. been arrested at the same time that flights from Europe were arrested (between February 26 and March 4, instead of by March 9), a substantial fraction of the transmission chains in Israel would have been prevented.

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A B Israel USA Europe China

Figure 3. Patterns of SARS-CoV-2 introduction into Israel. (A) Time-resolved phylogeny inferred using viral sequences from Israel (blue tips) and around the world (tips without dots). Lineages are colored by inferred region of circulation. Phylogeographic analysis reveals multiple introductions into Israel, mainly from the U.S. (B) Map of phylogenetically inferred introductions into Israel highlighting the dominance of the U.S. and to a lesser extent Europe as the geographic sources of SARS-CoV-2 introductions into Israel. Figures generated using NextStrain (Hadfield, et al. 2018).

As the pandemic spread, entry into Israel was restricted, and local transmissions became dominant. Transmission patterns into and between six various geographical regions in Israel (North district, Tel Aviv district, South coast district, Jerusalem district, and South district) are shown in Figure 4. While most local transmission occurred inside defined regions, transmission among distinct regions was also observed, such as, for example, movement between Jerusalem and the north district of Israel.

Figure 4. Spread of SARS-CoV-2 into and within Israel. (A) Map of Israel with geographic locations of samples, and inferred spread into Israel (colored lines) and inside Israel (blue lines). (B) Alternative view of spread into and inside Israel. Each line represents a transmission event inferred based on the phylogeny. Thicker lines indicate multiple transmission events.

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Phylodynamic modeling of viral spread in Israel To estimate the basic reproduction number of SARS-CoV-2 in Israel initially and then following the implementation of social distancing measures, we performed coalescent- based phylodynamic inference using PhyDyn (Methods). We note that existing phylodynamic analyses of SARS-CoV-2 have shown that the effective reproduction number RE of the virus has decreased over time, as quarantine and social distancing measures have been implemented within specific regions (Danesh, et al. 2020; Vaughan, et al. 2020; Volz, Baguelin, et al. 2020). However, many of these analyses have to date modeled reductions in RE as stemming from the depletion of susceptible individuals (Volz, Baguelin, et al. 2020), rather than from reductions in R0, the latter of which would be consistent with lowering of contact rates. Other analyses, particularly those that use the birth-death model approach for phylodynamic inference, have allowed for changes in R0 over time (Danesh, et al. 2020; Vaughan, et al. 2020), but cannot as easily accommodate structure in the infected host population (e.g., that some individuals are exposed but not yet infectious, and that transmission heterogeneity exists between infected individuals). Our phylodynamic analysis here, based heavily on existing coalescent-based model structures that have been applied to SARS-CoV-2 (Volz 2020), instead allows for this structure to be accommodated and for R0 to change in a piecewise fashion over time.

Our phylodynamic analysis assumes an underlying susceptible-exposed-infected-recovered (SEIR) epidemiological model for SARS-CoV-2 transmission dynamics and explicitly incorporates transmission heterogeneity (Methods). Recent epidemiological analyses have estimated considerable levels of SARS-CoV-2 transmission heterogeneity, with ~7-10% of infected individuals estimated to be responsible for 80% of secondary infections (Bi, et al. 2020; Endo, et al. 2020). Instead of assuming a given level of transmission heterogeneity for Israel, we instead performed phylodynamic inference of the SEIR model across a range of transmission heterogeneities ranging from ph = 1% to 20% of infected individuals being responsible for 80% of secondary infections. We estimated � prior to March 19 to be approximately 2.0 across this superspreading range, with estimates increasing towards R0 = 2.4 to 2.6 at extremely high levels of superspreading (ph = 1-2%) (Figure 5A). Across this superspreading range, we robustly estimated that quarantine measures had the effect of reducing R0 by approximately two-thirds (a = ~30%; Figure 5B; see Table S2 for model parameter priors and estimated values).

Figure 5C shows the cumulative number of SARS-CoV-2 cases by April 22, estimated by our phylodynamic analyses across the considered superspreading range. Estimates of the cumulative number of cases is highly sensitive to the level of assumed transmission heterogeneity, particularly at high levels of superspreading (ph = 1-5%). Comparison between these inferred cumulative cases and reported case numbers (dotted line in Figure 5C) indicates that SARS-CoV-2 transmission dynamics were driven by an extremely high level of viral superspreading. Specifically, if we assume almost complete case reporting, our phylodynamic analysis indicates that between 5-9% of infections are responsible for 80% of secondary infections; with lower assumed levels of case reporting, between 1-5% of infections would be responsible for this 80% of secondary infections.

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Figure 5. Estimated epidemiological parameters across different levels of transmission heterogeneity. The parameter � gives the fraction of infected individuals that are responsible for P = 80% of secondary infections. Higher � values correspond to less transmission heterogeneity. (A) Estimated R0 in Israel prior to March 19, 2020. (B) Estimated fraction by which R0 in Israel changed after March 19. (C) Estimated cumulative number of infected individuals in Israel on the date of the last sampled sequence (April 22, 2020). An infected individual is assumed to contribute to cumulative incidence at the end of their infectious period. Horizontal dotted line at N = 13,942 shows the cumulative number of reported cases on April 22, 2020 as given by the ECDC (https://opendata.ecdc.europa.eu/covid19/casedistribution/csv). In (A)-(C), only values that fall within the 95% highest posterior density intervals are shown.

Phylodynamic analysis further allows us to visualize inferred epidemiological dynamics. In Figure 6, we show inferred patterns of prevalence (Fig. 6A) and incidence (Fig. 6B) for three different assumed levels of viral superspreading. Inferred patterns of prevalence corroborate epidemiological findings that the number of cases started to decline in early April. Inferred patterns of cumulative incidence indicate that reporting rates were initially low, but improved considerably over the time course of viral spread. The ‘leveling off’ of cumulative incidence around late March/early April observed in both the reported case data and in our inferred epidemiological dynamics, ground-truthing the results of our phylodynamic analyses.

Figure 6. Epidemiological dynamics inferred using phylodynamic analysis. (A) Estimated number of currently infected individuals (Il + Ih) over time. (B) Estimated cumulative number of infected individuals. An infected individual is assumed to contribute to cumulative incidence at the end of their infectious period. Black dots show the cumulative number of reported cases in Israel over time, as given by the ECDC. Model-predicted numbers of infected individuals include both classes of infected individuals (Il + Ih). In (A) and (B), lines show median estimates of models with different levels of transmission heterogeneity: � = 0.01 (blue), 0.05 (pink), and 0.10 (green). Shaded regions show the 95% highest posterior density.

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Conclusions Overall, our findings highlight the use of genomic data to effectively track the spread of an emerging virus using phylogenetic and phylodynamic approaches that have been developed to study viral outbreaks. We have hereby succeeded in tracking the main transmission chains that led to SARS-CoV-2 spread in Israel, and applied phylodynamic analysis to infer key epidemiological parameters governing its spread. Our results suggest that superspreading events are a main feature of SARS-CoV-2 spread, suggesting that focused measures to reduce contacts of select individuals/social events could dramatically mitigate viral spread. Finally our results highlight how global connectivity allows for massive introductions of a virus, and emphasize how border control and shelter-in-place restrictions are crucial for halting viral spread.

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METHODS

Ethics statement An exemption from institutional review board approval was determined by the Israeli Ministry of Health as part of an active epidemiological investigation, based on use of anonymous data only and no medical intervention. The study was further approved by the Tel-Aviv University ethics committee (approval 0001274-1).

Details of samples & virus genome sequencing With the aim of generating a random sample of viral infections across the entire country, a total of 213 samples were retrieved from six major hospitals in Israel spanning the entire geography of Israel from south to north (Table 1, Table S1).

We obtained RNA extracted from nasopharyngeal samples. Sequencing was performed based on the V3 Arctic protocol (https://artic .network/ncov-2019). Briefly, reverse transcription and multiplex PCR of 109 amplicons was performed, and adapters were ligated to allow for sequencing. All samples were run on an Illumina Miseq using 250-cycle V2 kits in the Technion Genome Center (Israel).

Determining genome consensus sequences Sequencing reads were trimmed using pTrimmer, a multiplexing primer trimming tool (Zhang, et al. 2019), and then aligned to the reference genome of the SARS-CoV-2 (GenBank ID MN908947) using our AccuNGS pipeline (Gelbart, et al. 2019), which is based on BLAST (Altschul, et al. 1997), using an e-value of 10-9. The pipeline allows for consensus determination and variant calling. We considered substitutions at the consensus sequence (as compared to the reference) only if a given base was present in 80% of the aligned reads, and five or more reads aligned to the reference; bases where the majority of reads showed a substitution but that did not fulfill these two conditions were deemed uncertain. Similarly positions to which no reads were mapped were also deemed uncertain, and such positions were assigned with an “N”. All deletions were manually verified: (a) over 98% of the reads covering the deletion site mapped to both ends of the deletion (i.e, bore evidence of the deletions), (b) the deletion was based on over 40 independent reads (on average >1,000 reads), and (c) coverage was high at both ends of the deleted region. Only sequences that spanned 90% of the reference genome were retained, leading to the removal of one sequence (Table S1), and hence a new set of 212 Israeli sequences was generated here. Another two Israeli sequences already available on GISAID were added to the phylogenetic analysis, leading to a total of 214 sequences from Israel.

The collection dates of the 214 Israeli sequences used in our analysis ranged from February 23 through April 22, 2020. The number of sequences is thus approximately 1.5% of the total number of reported cases on April 22.

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Table 1. General statistics on samples collected and sequenced. Age group Number of samples 0-9 8 10-19 17 20-29 42 30-39 28 40-49 26 50-59 29 Age group Age 60-69 31 70-79 15 80-89 11 90 and up 3 unknown 2 Number of

Hospital City l samples a t i

p Barzilai Medical Center South coast district 30 s

o Samson Assuta Ashdod h South coast district 23 d University Hospital n a Hadassah University n Jerusalem district 62 o

i Hospital - Ein Kerem t a

c Poria Medical Center North district 26

Lo Sheba Medical Center Tel Aviv district 51 Soroka Medical Center South district 20

Number of samples x Female 101 Se Male 111

Phylogenetic analyses All available full-length SARS-CoV-2 genomes from outside of Israel (a total of 16,403 sequences) were retrieved from GISAID on May 5, 2020. All sequences from a non-human host as well as sequences with incomplete sampling date (YYYY-MM or YYYY-MM-XX) or a high level of uncertainty (>10% ambiguous bases marked as N) were removed. All available sequences were then down-sampled to 4,693 representative sequences across the globe using the latest build of NextStrain ncov pipeline (Hadfield, et al. 2018; Hadfield, et al. 2019) (https://github.com/nextstrain/ncov). 1195 of these 4,693 sequences were from the U.S., while 1991 were from Europe. The 212 new Israeli sequences were added to the tree.

Confidence in numbers and fractions of importation events Confidence in the relative number of importation events from the U.S. vs. Europe was assessed using two measures of confidence intervals, which were aimed at testing whether the set of exogenous sequences was biased, or whether the set of Israeli sequences was biased. First, we generated 1,000 samples of the exogenous (non-Israeli) sequences using a bootstrap approach and assessed the fraction of importation events in each sample. Second, we similarly bootstrapped the local (Israeli) sequences only and assessed the fraction of importation events in each sample. The reported confidence interval includes the lower bound and higher bound of both bootstrapping schemes.

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Down-sampling of global tree for phylodynamic analysis Following the initial sampling of the global tree described above, we applied a second sampling specifically for the phylodynamic analysis. The down-sampling followed the recommended guidelines described previously for SARS-CoV-2 (Volz, Boyd, et al. 2020). We used two sampling techniques: (i) Random time stratified sampling – we sampled a total of 100 sequences from outside of Israel across �=5 time intervals such that each time interval contained approximately 20 sequences. (ii) Closest sequence match – we will define � as the set of all sequences from Israel. We sample the exogenous set of sequences from the global tree with the minimal cophenetic distance between each Israeli sequence belonging to � as based on the maximum likelihood phylogeny. This allow including sequences closely related to sequences from Israel.

We next manually curated the sequences from Israel to ensure they represent a random sample across Israel. To this end we removed samples suspected to be from the same household, samples with consecutive identifiers, or identical samples with similar identifiers and similar dates. Only one sample from a given household was chosen randomly. This led to a removal of 6 sequences.

Following down-sampling and manual curation, a phylogenetic tree was inferred using the NextStrain pipeline (Hadfield, et al. 2018). The tree topology was validated as a legitimate representative of the global tree by performing 1,000 random samples containing 373 sequences from the global tree. The Kendall-Colijn metric (Kendall and Colijn 2016) was used to assess distance between each random sample and the original tree, allowing us to create a null distribution. The � parameter, which determines the trade-off between topology and branch length, was set to zero, thus accounting for the tree topology alone. The significance of down-sampling procedure was thus obtained by comparing the Kendall-Colijn metric of the down-sampled tree to the null distribution.

Rate of importations As described previously, strong global connectivity can result in a high number of independent seeding events (Chinazzi, et al. 2020), and we thus aimed at generating the distribution of importation dates (Volz, Boyd, et al. 2020). This was achieved based on the time-resolved phylogeny, which was then used to estimate the date of initial importation as well as the date on which the rate of new importations dropped. Given a down sampled ML tree � , we re-estimate a forest of trees using IQ Tree (Nguyen, et al. 2015) {� , … , � } such that each tree � is generated by randomly resolving polytomies in � . Each � is used to produce a time-based tree, � using TreeTime (Sagulenko, et al. 2018) with molecular clock rate �~�[0.0009 − 0.0015 ] substitutions/site/year. We deduce the distribution of all seeding events by taking the mid-branch date for each node leading to an Israeli tip for all trees. Both IQ Tree and TreeTime were executed using the Augur python package.

Phylodynamic Analysis Phylodynamic analyses were conducted using BEAST2 v2.6.2 (Bouckaert, et al. 2019) and PhyDyn v1.3.6 (Volz and Siveroni 2018). An HKY substitution model with a lognormal prior for � with mean log(�) = 1.0 and standard deviation of log(�) = 1.25 was used. We assumed no sites to be invariant and used an exponential prior for � with a mean of 1.0. A strict molecular clock with a uniform prior between 0.0007 and 0.002 substitutions/site/year was

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used. A uniform prior was used for nucleotide frequencies. The down-sampled maximum likelihood tree generated using IQ Tree was used as a starting tree.

PhyDyn is a coalescent-based inference approach implemented in BEAST2, allowing for the integration over phylogenetic uncertainty (Volz 2012; Volz and Siveroni 2018). The program requires specification of an underlying epidemiological model, as well as any priors on parameters that will be estimated. In line with recent analyses (sarscov2.phylodynamics.org), we assumed that the epidemiological dynamics of SARS-CoV- 2 were governed by Susceptible-Exposed-Infected-Recovered (SEIR) dynamics. Transmission heterogeneity has previously been described for viral pathogens including SARS-CoV-1 (Lloyd-Smith, et al. 2005) and appears to be important in the transmission dynamics of SARS- CoV-2 (Bi, et al. 2020; Endo, et al. 2020). To account for the possibility of transmission heterogeneity, as in previous work (sarscov2.phylodynamics.org), we modeled two classes of infected individuals: one with low transmissibility Il and one with high transmissibility Ih. Mathematically, the epidemiological model is given by

��⁄�� = −��(�/�) − �� (�/�) � � �� = � � + � � − � � � � ��⁄�� = (1 − �)�� − �� ⁄�� = �� − �� ⁄�� = �� +��

We set as fixed the host population size to the population size of Israel, according to the European Centre for Disease Prevention and Control (N = 8,883,800), the average duration of time an individual spends in the exposed class (1/� = 3 days), and the average duration of time an individual spends in the infected (infectious) class (1/� = 5.5 days). These rates are based on a study that inferred transmissibility over the course of infection based on data from established SARS-CoV-2 transmission pairs (He, et al. 2020). R0 in this model is given by (�� + �(1 − �))/� , where � is the fraction of exposed individuals who transition to the � class. Instead of independently parameterizing � and �, we defined (as in previous work) the relative transmissibility of infected individuals in the Ih and Il classes by the parameter � = �/�. We defined a parameter P as the fraction of secondary infections that were caused by a fraction �of the most transmissible infected individuals and set P to 0.8. Based on set values of P and �, we calculated � as( )/( − 1). As such, we could easily parameterize the model across various levels of transmission heterogeneity, with a fraction � of infected individuals being responsible for 80% of secondary infections. Existing epidemiological analysis indicate that � is on the order of 7-10% (Bi, et al. 2020; Endo, et al. 2020) indicative of even more transmission heterogeneity than given by the 20/80 rule (Woolhouse et al., PNAS, 1997). We focused on the range of �between 1-10% in our phylodynamic analyses.

Again based on existing analyses (sarscov2.phylodynamics.org), we included an external reservoir, Y, in our analysis to allow for multiple introduced clades into Israel to be jointly considered. We assume symmetric migration of individuals in the �, �, and � classes in and out of Israel based on a per capita migration rate �. An exponential prior with a mean of 10 and an upper limit of 10 was used for �. Based on the results of the importation analysis described above, we assumed that the migration rate decreased to 25% of its original value after March 20, 2020. As migration is assumed to be symmetrical in and out of Israel it does not affect the focal SEIR model dynamics, however, it influences the probability that a given lineage’s geographic state is assigned to Israel. We fix the rate of removal of individuals from

13 medRxiv preprint doi: https://doi.org/10.1101/2020.05.21.20104521; this version posted May 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

Y to be 1/(1/� + 1/�) and estimate the rate of entry into Y, �, using a lognormal distribution with mean log(�) = 3.6 and standard deviation log(�) = 1.

In our model, we estimated a piecewise R0 by estimating an initial R0 that was in effect until March 19, 2020 slightly after strong social distancing measures were implemented, along with a factor � by which R0 changed on March 19. We set the prior on R0 to a lognormal distribution with mean log (R0) of 1.5 and standard deviation of log (R0) of 0.5. We set the prior on � to be uniform between 0 and 2, thereby allowing R0 to either increase, decrease, or remain unchanged after March 19. An exponential prior with mean 1.0 was used for the initial size of the � class. The � and � were assumed to be negligibly small at the beginning of the SEIR dynamics. The PhyDyn � parameter was set to 2019.7 and a constant population size coalescent model was used prior to this date when proposed trees had earlier root dates. SEIR dynamics were assumed to begin on February 1st. Sequences sampled from Israel were randomly assigned to � with probability � and to � with probability 1 − �. XML files to run both BEAST2 and PhyDyn were generated using a custom Python 3 script which was designed to edit a template XML file originally generated with BEAUti and manually edited. MCMC chains for each parameter set were run for at least 1.9 million steps. Convergence was assessed based on visual inspection of parameter traces. Longer MCMC chains and additional replicates are currently being conducted. The first 50% of MCMC steps were discarded as burn-in. BEAST2 log and tree files were combined using LogCombiner. Maximum clade credibility trees were generated using TreeAnnotator. BEAST2 and PhyDyn outputs were visualized using Python 3, Matplotlib (Hunter 2007), Seaborn, and Baltic (https://github.com/evogytis/baltic).

Data and code availability The assembled SARS-CoV-2 genomes (consensus sequences) were uploaded to GISAID (Table S1). Submission of the raw sequencing data to Sequence Read Archive (SRA) is pending. Code for phylodynamic analysis and model XML configuration, as well as scripts to analyze outputs are available at: https://github.com/SternLabTAU/SARSCOV2NGS.

Acknowledgements

We wish to thank Dr. Boaz Lev at the Israeli Ministry of Health and Dr. Tal Katz-Ezov at the Technion Genome Center, as well as Stern lab members for their support during an ongoing pandemic and various stages of lockdown. This work was funded by the Israeli Science Foundation (1333/16) and by a generous donation from the Milner foundation and from AppFlyer. This study was supported in part by a fellowship to DM, TK and OT from the Edmond J. Safra Center for Bioinformatics at Tel-Aviv University.

14 medRxiv preprint doi: https://doi.org/10.1101/2020.05.21.20104521; this version posted May 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

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17 medRxiv preprint doi: https://doi.org/10.1101/2020.05.21.20104521; this version posted May 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

Table S1. Details of samples sequenced.

Geog. Ct Ct Genome location of Sample ID Ct E RdRp Ct N average Sex Age Date Hospital coverage sample 1639953 28.5 30.5 32 30.18 M 10-19 26/3/20 Poria 0.996 North 1639996 23.1 24.4 26 24.45 M 20-29 26/3/20 Poria 0.996 North 2020038 22.5 22.46 F 50-59 17/3/20 Hadassah 0.994 Tel Aviv 2020051 30.9 30.87 M 40-49 17/3/20 Hadassah 0.976 Tel Aviv 2020063 28.4 28.39 F 20-29 17/3/20 Hadassah 0.985 Jerusalem 2020068 24.8 24.78 F 20-29 17/3/20 Hadassah 0.986 Jerusalem 2020069 28.2 28.24 F 30-39 17/3/20 Hadassah 0.987 Jerusalem 2020078 21.5 21.5 M 50-59 17/3/20 Hadassah 0.989 Jerusalem 2020084 24.9 24.87 M 60-69 17/3/20 Hadassah 0.994 Jerusalem 2020087 21.5 21.48 M 20-29 17/3/20 Hadassah 0.996 Jerusalem 2023920 18.6 18.56 M 40-49 17/3/20 Hadassah 0.996 Jerusalem 2023922 28 28 F 20-29 17/3/20 Hadassah 0.979 Jerusalem 2046129 23.1 24.2 27 24.88 M 20-29 31/3/20 Poria 0.996 North 2046171 29.6 30.8 33 31.24 F 50-59 31/3/20 Poria 0.954 North 2046434 19.5 20.6 24 21.28 F 50-59 1/4/20 Poria 0.996 North 2046548 28.5 31.1 34 31.01 M 40-49 1/4/20 Poria 0.991 North 2046614 24.4 26.2 28 26.24 F 30-39 2/4/20 Poria 0.996 North 2046616 20.5 22.3 25 22.47 F 70-79 2/4/20 Poria 0.996 North 2046815 13.8 16.5 18 16.08 F 80-89 4/4/20 Poria 0.994 North 2047004 23 24.5 27 24.81 M 30-39 27/3/20 Poria 0.996 North 2047011 28.5 30.2 32 30.24 M 20-29 26/3/20 Poria 0.952 North 2047016 25.7 26.7 29 26.99 F 0-9 26/3/20 Poria 0.996 North 2047145 10.3 11.8 15 12.38 F 30-39 26/3/20 Poria 0.996 North 2047188 13.6 15.3 18 15.48 M 20-29 26/3/20 Poria 0.996 North 2047189 9.75 11.7 14 11.87 M 20-29 26/3/20 Poria 0.996 North 2047364 20.8 22.8 25 22.68 F 60-69 28/3/20 Poria 0.996 North 2047392 27.6 29.9 31 29.42 F 30-39 29/3/20 Poria 0.966 North 2047418 24 25.4 28 25.67 M 0-9 29/3/20 Poria 0.996 North 2047567 26.8 28.7 31 28.97 F 30-39 29/3/20 Poria 0.978 North 2047586 22.8 24.1 27 24.71 F 20-29 29/3/20 Poria 0.996 North 2047604 22.7 24 26 24.32 M 50-59 29/3/20 Poria 0.996 North 2047738 20 22.1 25 22.21 M 10-19 30/3/20 Poria 0.996 North 2047749 19.3 20.7 23 21.03 F 40-49 30/3/20 Poria 0.996 North 2047772 23.8 25.7 26 25.3 F 30-39 30/3/20 Poria 0.996 North 2047883 21.1 22.9 25 22.87 M 60-69 31/3/20 Poria 0.996 North 2047927 32 33.7 36 33.74 F 60-69 31/3/20 Poria 0.918 North 2086001 28.4 28.4 F 10-19 1/4/20 Hadassah 0.988 Jerusalem 2086004 24.6 24.63 F 20-29 1/4/20 Hadassah 0.993 Jerusalem 2086008 20.2 20.24 M 90+ 1/4/20 Hadassah 0.996 Jerusalem 2086012 24.4 24.39 M 20-29 1/4/20 Hadassah 0.988 Jerusalem 2086022 27.9 27.88 M 20-29 1/4/20 Hadassah 0.986 Jerusalem 2086033 28.8 28.79 F 60-69 1/4/20 Hadassah 0.991 Jerusalem 2086034 30 30.01 F 20-29 1/4/20 Hadassah 0.981 Jerusalem 2086045 20 19.99 M 50-59 1/4/20 Hadassah 0.996 Jerusalem medRxiv preprint doi: https://doi.org/10.1101/2020.05.21.20104521; this version posted May 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

2089366 20.4 20.36 M 20-29 1/4/20 Hadassah 0.996 Jerusalem 2089368 25.6 25.62 M 60-69 1/4/20 Hadassah 0.985 Jerusalem 2089375 27.5 27.54 M 10-19 1/4/20 Hadassah 0.992 Jerusalem 2089380 30.1 30.14 F 60-69 1/4/20 Hadassah 0.979 Jerusalem 2089383 29.8 29.79 M 30-39 1/4/20 Hadassah 0.989 Jerusalem 2089697 28.3 28.27 F 20-29 1/4/20 Hadassah 0.989 Jerusalem 2089698 28.6 28.58 F 50-59 1/4/20 Hadassah 0.984 Jerusalem 2089712 25.5 25.52 M 20-29 1/4/20 Hadassah 0.989 Jerusalem 2089718 20.6 20.6 F 30-39 1/4/20 Hadassah 0.996 Jerusalem 2089723 28.6 28.55 M 30-39 1/4/20 Hadassah 0.992 Jerusalem 2089812 23.3 23.29 F 20-29 1/4/20 Hadassah 0.995 Jerusalem 2089839 25.5 25.5 M 60-69 1/4/20 Hadassah 0.989 Jerusalem 2089852 25.5 25.53 F 60-69 1/4/20 Hadassah 0.989 Jerusalem 2089861 18.3 18.31 M 70-79 1/4/20 Hadassah 0.996 Jerusalem 2089863 18.8 18.8 M 30-39 1/4/20 Hadassah 0.996 Jerusalem 2089866 20.7 20.7 M 30-39 1/4/20 Hadassah 0.996 Jerusalem 2099018 30.3 30.34 F 60-69 2/4/20 Hadassah 0.980 Jerusalem 2099019 27.5 27.48 M 20-29 2/4/20 Hadassah 0.992 Jerusalem 2099159 27.3 27.3 F 10-19 2/4/20 Hadassah 0.988 Jerusalem 2099251 23 22.98 F 20-29 2/4/20 Hadassah 0.996 Jerusalem 2099416 29 28.98 M 20-29 2/4/20 Hadassah 0.983 Jerusalem 2099421 20.5 20.45 M 50-59 2/4/20 Hadassah 0.996 Jerusalem 2107132 29.9 29.91 F 50-59 14/4/20 Hadassah 0.996 Jerusalem 2107137 19.6 19.6 F 10-19 14/4/20 Hadassah 0.996 Jerusalem 2107681 22.3 22.3 F 30-39 14/4/20 Hadassah 0.996 Jerusalem 2113155 25.6 25.55 M 0-9 15/4/20 Hadassah 0.996 Jerusalem 2113161 25.9 25.92 M 70-79 15/4/20 Hadassah 0.996 Jerusalem 2113173 29.8 29.78 M 10-19 15/4/20 Hadassah 0.996 Jerusalem 2113174 26.4 26.42 M 70-79 15/4/20 Hadassah 0.996 Tel Aviv 2113178 26.6 26.62 M 20-29 15/4/20 Hadassah 0.996 Jerusalem 2113255 29.1 29.14 F 60-69 14/4/20 Hadassah 0.994 Jerusalem 2113256 29.7 29.65 F 10-19 14/4/20 Hadassah 0.996 Jerusalem 2113601 25.1 25.07 M 0-9 15/4/20 Hadassah 0.996 Jerusalem 2113603 21.7 21.72 M 70-79 15/4/20 Hadassah 0.996 Jerusalem 2113678 29.8 29.78 M 0-9 15/4/20 Hadassah 0.996 Tel Aviv 2115701 26 25.96 F 10-19 16/4/20 Hadassah 0.996 Jerusalem 2115964 28.4 28.35 M 10-19 16/4/20 Hadassah 0.996 Tel Aviv 2115968 26.8 26.83 F 20-29 16/4/20 Hadassah 0.996 Tel Aviv 2115976 28.2 28.17 M 60-69 16/4/20 Hadassah 0.985 Tel Aviv 2115980 24.5 24.49 F 20-29 16/4/20 Hadassah 0.912 North 2115990 30.2 30.15 F 50-59 16/4/20 Hadassah 0.996 Jerusalem 2116859 29.6 29.6 F 10-19 20/4/20 Hadassah 0.953 Jerusalem 2123853 28.1 28.05 M 70-79 20/4/20 Hadassah 0.996 Jerusalem 2123863 27.5 27.47 M 80-89 20/4/20 Hadassah 0.996 Jerusalem 13075703 24 25.6 28 25.98 F 20-29 29/3/20 Sheba 0.996 Tel Aviv 13075719 27.7 28.9 31 29.16 F 20-29 29/3/20 Sheba 0.996 Tel Aviv 13075735 26.8 28.4 30 28.47 M 40-49 30/3/20 Sheba 0.996 Tel Aviv 13075782 29.1 30.5 33 30.85 F 40-49 30/3/20 Sheba 0.992 Tel Aviv 13075788 27.8 29.3 31 29.4 F 40-49 30/3/20 Sheba 0.996 Tel Aviv medRxiv preprint doi: https://doi.org/10.1101/2020.05.21.20104521; this version posted May 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

13075790 27.2 28.8 30 28.7 M 50-59 30/3/20 Sheba 0.996 Tel Aviv 13075832 17.5 18.6 20 18.7 M 30-39 30/3/20 Sheba 0.996 Tel Aviv 13075879 18.6 20 22 20.27 M 50-59 30/3/20 Sheba 0.993 Tel Aviv 13075882 18.6 20.4 21 20.1 F 20-29 30/3/20 Sheba 0.996 Tel Aviv 13075914 17.1 18.5 20 18.39 F 50-59 30/3/20 Sheba 0.996 Tel Aviv 13077377 27 29 29 28.33 M 40-49 2/4/20 Sheba 0.996 Tel Aviv 13077383 26 26 28 26.67 F 40-49 2/4/20 Sheba 0.984 Jerusalem 13077413 24 25 26 25 M 70-79 3/4/20 Sheba 0.996 Tel Aviv 13077494 28 29 31 29.33 M 20-29 2/4/20 Sheba 0.856 South Coast 13077497 21 22 24 22.33 F 60-69 2/4/20 Sheba 0.996 South Coast 13077498 17 18 21 18.67 M 20-29 3/4/20 Sheba 0.996 South Coast 13077510 21 22 25 22.67 M 50-59 3/4/20 Sheba 0.993 Jerusalem 13077511 25 26 28 26.33 M 20-29 3/4/20 Sheba 0.986 Jerusalem 13077558 19 20 22 20.33 F 30-39 3/4/20 Sheba 0.996 Tel Aviv 13077560 27 28 30 28.33 F 80-89 3/4/20 Sheba 0.974 Tel Aviv 13077562 15 17 19 17 F 50-59 3/4/20 Sheba 0.988 Tel Aviv 13077564 22 23 25 23.33 F 50-59 3/4/20 Sheba 0.992 Tel Aviv 13077711 27 28 30 28.33 F 30-39 3/4/20 Sheba 0.995 Tel Aviv 13077723 22 23 25 23.33 M ? 3/4/20 Sheba 0.989 Tel Aviv 13077726 20 20 22 20.67 F 60-69 3/4/20 Sheba 0.996 Tel Aviv 13077803 28 29 32 29.67 F 30-39 4/4/20 Sheba 0.981 South Coast 13077823 15 17 19 17 F 10-19 4/4/20 Sheba 0.996 South Coast 13077840 23 25 27 25 M 20-29 4/4/20 Sheba 0.991 Jerusalem 13077846 19 20 23 20.67 F 0-9 4/4/20 Sheba 0.996 Tel Aviv 13077847 24 26 27 25.67 M 10-19 4/4/20 Sheba 0.986 Tel Aviv 13077875 18 19 21 19.33 F 40-49 4/4/20 Sheba 0.996 Tel Aviv 13077882 24 26 27 25.67 M 40-49 4/4/20 Sheba 0.987 Jerusalem 51137031 18.58 M 30-39 1/3/20 Soroka 0.996 Tel Aviv 51137844 27.6 F 30-39 17/3/20 Soroka 0.983 South 51140028 20.56 F 50-59 17/3/20 Soroka 0.996 North 51140068 22.8 M 30-39 18/3/20 Soroka 0.988 South 51140271 28.16 F 40-49 18/3/20 Soroka 0.971 South Coast 51140279 25.76 F 20-29 18/3/20 Soroka 0.976 South Coast 51140315 23.41 M 60-69 18/3/20 Soroka 0.996 South 51140539 19.4 F 50-59 19/3/20 Soroka 0.996 South 51140836 24.5 M 30-39 20/3/20 Soroka 0.986 South 51141014 23.08 F 90+ 22/3/20 Soroka 0.996 South 51141121 29.05 M 70-79 22/3/20 Soroka 0.989 South 51141225 18.58 F 40-49 22/3/20 Soroka 0.996 South 51144342 25.59 M 90+ 30/3/20 Soroka 0.976 South 51145198 25.49 M 80-89 1/4/20 Soroka 0.989 South 51145482 27.92 F 40-49 5/4/20 Soroka 0.992 Tel Aviv 51146355 29.24 F 80-89 4/4/20 Soroka 0.989 South 51146500 21.79 M 40-49 5/4/20 Soroka 0.989 Tel Aviv 51146503 23.75 F 30-39 5/4/20 Soroka 0.993 Jerusalem 51146669 24.41 M 10-19 5/4/20 Soroka 0.994 Tel Aviv 51146683 24.8 M 10-19 5/4/20 Soroka 0.965 Tel Aviv 130710062 28 28 28 28 M 40-49 14/4/20 Sheba 0.991 Tel Aviv 130710067 23 24 24 23.67 M 60-69 14/4/20 Sheba 0.996 Tel Aviv medRxiv preprint doi: https://doi.org/10.1101/2020.05.21.20104521; this version posted May 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

130710097 29 31 32 30.67 M 70-79 15/4/20 Sheba 0.996 Tel Aviv 130710099 33 33 34 33.33 M 60-69 15/4/20 Sheba 0.979 Tel Aviv 130710157 20 21 24 21.67 M 70-79 15/4/20 Sheba 0.996 Tel Aviv 130710159 27 28 29 28 F 80-89 15/4/20 Sheba 0.990 Tel Aviv 130710211 18 19 20 19 F 70-79 16/4/20 Sheba 0.996 Tel Aviv 130710217 22 23 26 23.67 M 50-59 16/4/20 Sheba 0.996 Tel Aviv 130710390 28 29 30 29 F 30-39 17/4/20 Sheba 0.996 Tel Aviv 130710414 20 21 22 21 M 20-29 17/4/20 Sheba 0.996 Tel Aviv 130710643 31 31 31 31 M 40-49 19/4/20 Sheba 0.986 Tel Aviv 130710644 29 30 31 30 F 80-89 19/4/20 Sheba 0.985 Tel Aviv 130710716 30 31 31 30.67 F 60-69 19/4/20 Sheba 0.989 Tel Aviv 130711082 18.5 20 22 20.17 F 60-69 20/4/20 Sheba 0.996 Tel Aviv 130711104 27 29 29 28.33 F 80-89 20/4/20 Sheba 0.993 Tel Aviv 130711112 31 32 31 31.33 F 80-89 21/4/20 Sheba 0.991 Tel Aviv 130711116 25 27 25 25.67 F 60-69 21/4/20 Sheba 0.996 Tel Aviv 130711367 29 27 27 27.67 F 60-69 22/4/20 Sheba 0.996 North 130711417 32 31 30 31 M 60-69 22/4/20 Sheba 0.974 Tel Aviv 701002313 27 M 50-59 21/3/20 Barzilai 0.996 South Coast 701002314 21 M 20-29 21/3/20 Barzilai 0.996 South Coast 701002317 25 M 50-59 21/3/20 Barzilai 0.996 South Coast 701002327 19 M 50-59 22/3/20 Barzilai 0.996 South Coast 701002334 21 M 70-79 22/3/20 Barzilai 0.996 South Coast 701002403 31 M 40-49 23/3/20 Barzilai 0.996 South Coast 701002407 27 M 40-49 23/3/20 Barzilai 0.959 South Coast 701002426 25 M 60-69 24/3/20 Barzilai 0.996 South Coast 701002431 18 M 20-29 24/3/20 Barzilai 0.996 South Coast 701002440 26 F 20-29 24/3/20 Barzilai 0.996 South Coast 701002442 18 M 30-39 24/3/20 Barzilai 0.996 South Coast 701002455 30 F 20-29 24/3/20 Barzilai 0.992 South Coast 701002456 30 F 60-69 24/3/20 Barzilai 0.980 South Coast 701002458 21 M 40-49 24/3/20 Barzilai 0.996 South Coast 701002462 21 M 70-79 24/3/20 Barzilai 0.996 South Coast 701002489 27 M 40-49 25/3/20 Barzilai 0.996 South Coast 701002504 21 M 70-79 25/3/20 Barzilai 0.996 South Coast 701002538 28 M 70-79 25/3/20 Barzilai 0.996 South Coast 701002540 21 F 40-49 25/3/20 Barzilai 0.996 South Coast 701002550 24 M 30-39 26/3/20 Barzilai 0.996 South Coast 701002555 23 F 40-49 26/3/20 Barzilai 0.996 South Coast 701002556 22 F 60-69 26/3/20 Barzilai 0.996 South Coast 701002561 28 M 50-59 26/3/20 Barzilai 0.996 South Coast 701002591 24 F 50-59 26/3/20 Barzilai 0.996 South Coast 701002666 26 M 40-49 26/3/20 Barzilai 0.996 South Coast 701002681 24 M 60-69 27/3/20 Barzilai 0.996 South Coast 701002752 27 M 10-19 28/3/20 Barzilai 0.987 South Coast 701002768 21 M 50-59 28/3/20 Barzilai 0.996 South Coast 701002786 27 M 60-69 29/3/20 Barzilai 0.996 South Coast 701002792 25 M 50-59 29/3/20 Barzilai 0.995 South Coast 990059202 26.9 28.4 27 27.4 M 60-69 25/3/20 Assuta 0.996 South Coast 990059203 26.5 28.6 27 27.2 F 80-89 25/3/20 Assuta 0.996 South Coast medRxiv preprint doi: https://doi.org/10.1101/2020.05.21.20104521; this version posted May 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

990059204 28.4 30.1 28 28.97 F 30-39 25/3/20 Assuta 0.976 South Coast 990059217 29.1 31.4 32 30.9 M 60-69 25/3/20 Assuta 0.995 South Coast 990059230 26.5 29.7 29 28.5 F 0-9 25/3/20 Assuta 0.972 South Coast 990059231 24.9 28 28 27 M 30-39 25/3/20 Assuta 0.996 South Coast 990059232 24.5 26.7 28 26.3 M 10-19 25/3/20 Assuta 0.996 South Coast 990059233 19.7 21.8 23 21.43 F 50-59 25/3/20 Assuta 0.996 South Coast 990059237 28.3 30.6 32 30.23 F 0-9 25/3/20 Assuta 0.989 South Coast 990059238 24.3 26.3 27 25.83 F 20-29 25/3/20 Assuta 0.996 South Coast 990059244 27.9 30.8 31 29.97 F ? 25/3/20 Assuta 0.938 South Coast 990059251 24.7 28 28 26.9 F 50-59 25/3/20 Assuta 0.996 South Coast 990059252 24.4 26.8 28 26.27 F 20-29 25/3/20 Assuta 0.996 South Coast 990300681 22.9 26.4 27 25.37 F 60-69 30/3/20 Assuta 0.995 South Coast 990300691 29.3 31.7 32 31 M 20-29 31/3/20 Assuta 0.970 South Coast 990300724 23.7 26.6 26 25.53 M 80-89 1/4/20 Assuta 0.993 South Coast 990300860 19.3 21.9 0 20.6 M 20-29 2/4/20 Assuta 0.996 South Coast 990307712 26 27.3 28 26.97 F 20-29 26/3/20 Assuta 0.996 South Coast 990333068 30.1 32.7 34 32.13 M 60-69 24/3/20 Assuta 0.963 South Coast 990333189 29.3 31.4 32 30.9 M 50-59 26/3/20 Assuta 0.950 South Coast 990333193 20.7 22.6 24 22.43 F 40-49 26/3/20 Assuta 0.996 South Coast 990333263 36.4 0 0 36.4 M 30-39 31/3/20 Assuta 0.660 South Coast 990430264 29.3 31.7 33 31.17 F 40-49 29/3/20 Assuta 0.970 South Coast 990430265 29.6 32.2 33 31.7 F 30-39 29/3/20 Assuta 0.994 South Coast medRxiv preprint doi: https://doi.org/10.1101/2020.05.21.20104521; this version posted May 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license .

Table S2. Model parameter priors and estimated values

Posterior (Median (95% HPD))

Parameter Prior p h = 0.01 p h = 0.02 p h = 0.05 p h = 0.07 p h = 0.08 p h = 0.09 p h = 0.10 7.7E-4 7.5E-4 7.5E-4 Clock rate Uniform(0.0007, 0.002) (7.0E-4, 7.3E-4 (7.0E- 7.4E-4 (7.0E- 7.5E-4 (7.0E-4, 7.8E-4 (7.1E- (7.0E-4, (7.0E-4, 8.4E-4) 4, 8.1E-4) 4, 8.2E-4) 8.5E-4) 4, 8.7E-4) 8.6E-4) 8.2E-4) κ Lognormal(mean = 1.0, sd 3.7 (3.1, 3.7 (3.0, 3.7 (3.1, 3.7 (3.0, = 1.25) 4.5) 4.4) 3.7 (3.0, 4.4) 3.7 (3.0, 4.5) 3.7 (3.1, 4.5) 4.5) 4.3) γ 0.039 0.047 0.039 0.039 0.034 Exponential(mean = 1.0) (0.003, (0.003, 0.040 (0.002, 0.042 (0.003, (0.002, (0.005, (0.003, 0.082) 0.109) 0.104) 0.010) 0.098) 0.088) 0.080) R 0 Lognormal(mean = 1.5, sd 2.7 (2.5, 2.4 (2.3, 2.0 (1.9, 2.1 (1.9, = 0.5) 2.9) 2.5) 2.1 (2.0, 2.3) 2.1 (1.9, 2.2) 2.0 (1.9, 2.2) 2.2) 2.2) α Uniform(0, 2) 0.26 (0.15, 0.30 (0.15, 0.27 (0.15, 0.36 (0.19, 0.36 (0.16, 0.32 (0.18, 0.32 (0.16, 0.49) 0.51) 0.49) 0.63) 0.66) 0.58) 0.65) E init Exponential(mean = 1.0) 21 (14, 30) 23 (19, 27) 21 (15, 32) 19 (14, 26) 18 (12, 27) 17 (12, 23) 12 (9, 16) Y init 0.021 0.029 0.015 0.056 Exponential(mean = 1.0) (0.018, (0.029, 0.080 (0.026, 0.018 (0.012, (0.012, (0.040, 0.12 (0.07, 0.036) 0.049) 0.122) 0.035) 0.019) 0.078) 0.19) ρ Lognormal(mean = 3.6, sd = 1.0) 27 (25, 28) 25 (24, 26) 21 (20, 24) 23 (22, 25) 23 (22, 24) 21 (20, 22) 19 (18, 20) η Exponential(mean = 10 ) 9.4 (6.7, 9.7 (8.3, 9.2 (6.8, 9.5 (7.6, 9.7 (8.1, 10.0) 10.0) 9.5 (7.4, 10.0) 9.5 (7.5, 10.0) 10.0) 10.0) 10.0)